Cardiovascular (CV) disease is the leading cause of death in the western world. The increase in CV disease has not only led to an increase in mortality but an increase in CV morbidity. One of the major forms of CV morbidity is heart failure (HF). HF is a complex clinical syndrome characterized by high mortality, frequent hospitalization, poor quality of life, and a complex therapeutic regimen. In the US alone, HF affects nearly 5 million people and there are an estimated 400,000 newly diagnosed cases annually (American Heart Association, 2006, Heart Disease and Stroke Statistics, 2006 Update, Dallas, Tex.). HF is responsible for more hospitalizations than all forms of cancer combined and is the leading cause of hospitalization in patients older than 65 years of age (American Heart Association, 2006, Heart Disease and Stroke Statistics, 2006 Update, Dallas, Tex.; Adams et al., 2006, J Cardiac Fail, 12(1):10-38.). In-hospital mortality is excessive and readmission is distressingly common, despite advances in pharmacological and device therapies. This need for increased hospitalizations results in enormous direct costs and more is spent annually on the diagnosis and treatment of HF by Medicare than on any other Medicare diagnosis (American Heart Association, 2006, Heart Disease and Stroke Statistics, 2006 Update, Dallas, Tex.; Adams et al., 2006, J Cardiac Fail, 12(1):10-38.). HF is classified as HF with reduced ejection fraction (HF-REF) versus HF with preserved ejection fraction (HF-PEF).
Therapies targeted at improving outcomes in HF-REF have been well studied over the past two decades leading to an improvement in morbidity, mostly in the form of a decrease in re-hospitalization for HF-REF with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and β blockers (Cohn et al., 1991, N Engl J Med, 325:303-310; Pfeffer et al., 2003, Lancet, 362:759-766; The CONSENSUS Trial Study Group, 1987, N Engl J Med, 316:1429-1435; The SOLVD Investigators, 1992, N Engl J Med, 327:685-691; The SOLVD Investigators, 1991, N Engl J Med, 325:293-302; Packer at al., 2002, Circulation, 106: 2194-2199).
However, despite the availability of various therapies, HF deaths have continued to rise steadily. This increase has been attributed to the aging of the population and the better survival of underlying diseases, such as for example myocardial infarction, resulting in more incidence of HF as well as the availability of more treatment options which allow HF patients to live longer (American Heart Association, 2006, Heart Disease and Stroke Statistics, 2006 Update, Dallas, Tex.).
It is estimated that 35% to 60% of patients diagnosed with HF have normal or near normal left ventricle ejection fraction (LVEF) (ACC/AHA Guideline, 2005, Circulation, 112:1825-1852). In HF patients with preserved ejection fraction (HF-PEF), there is an impairment of cardiac relaxation resulting in an abnormal ventricular filling (Adams et al., 2006, J Cardiac Fail, 12(1):10-38). Such patients differ from those with HF with reduced ejection fraction (HF-REF) in a number of important ways. Patients with HF-PEF tend to be older and female, and their conditions are more likely to be associated with hypertension rather than with ischemia, and lower percentage of patients have prior myocardial infarction as compared to patients with reduced ejection fraction (Bhatia et al., 2006, N Engl J Med, 355:260-290).
Pathophysiologic mechanisms that have been implicated in HF-PEF include abnormal diastolic dysfunction with resultant increased ventricular filling pressures, atrial enlargement, increased vascular stiffness, and abnormal systolic function despite relatively preserved ejection fraction.
Left ventricular hypertrophy or concentric remodeling and left atrial enlargement are present in a majority of patients. In addition, left atrial size and left ventricular mass are independently associated with an increased risk of morbidity and mortality. Therefore, the presence of structural remodeling is not only of diagnostic importance but also provide important prognostic insights (Zile et al., 2011, Circulation, 124(23):2491-501). As such a remodeled left atrium indicates increased left ventricular filling pressures that characterize heart failure but also serves as substrate for atrial fibrillation. A treatment that affects or even reduces the remodeling of the cardiac cavities is expected to address the underlying pathophysiology and hence to prevent disease progression.
Atrial Fibrillation (AF) is the most common arrhythmia in patients with Heart Failure (HF); its prevalence increases with the severity of HF, and its occurrence is frequently associated with symptom deterioration and increased morbidity.
Because the renin-angiotensin-aldosterone system (RAAS) is involved in many of the processes associated with HF-PEF, inhibitors of RAS system have been of particular interest as a potential therapeutic intervention for these patients. However, several recently completed large, prospective clinical trials (PEP-CHF, CHARM-Preserved, and I-PRESERVE trials) have not demonstrated a significant benefit of blocking RAAS in improving mortality and morbidity in this population (Cleland et al., 2006, Eur J Heart Failure, 8: 105-110; Yussef et al., 2003, Lancet, 362:777-781; Massie et at, 2008, N Engl J Med., 359(23):2456-67), though these agents have showed favorable effects in patients with a reduced EF.
As a result, to date, there is no proven pharmacologic therapy for the HF-PEF population. Consequently, many of the guidelines for heart failure treatment do not address this group of patients (American Heart Association, 2006, Heart Disease and Stroke Statistics, 2006 Update, Dallas, Tex.; ESC Guidelines, 2008, Eur Heart J, 29:2388-2442). Rather, treatment options have been focused on treating co-morbidities, such as hypertension or diabetes. Just recently, in 2013, the American Heart Association has added to consider the administer Angiotensin Receptor Blockers (ARBs) to decrease hospitalizations for patients with HF-PEF.
Therefore it would be highly advantageous to provide a new treatment option and indeed providing relief or at least improvement for HF patients, and in particular for HF patients with preserved ejection fraction (HF-PEF).